Journal
MOLECULAR PHARMACEUTICS
Volume 14, Issue 7, Pages 2314-2322Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.7b00178
Keywords
supersaturated solution; H-1 NMR measurement; phase separation; hypromellose; nifedipine
Funding
- Research on Development of New Drugs from Japan Agency of Medical Research and Development (AMED)
- Japan Society for the Promotion of Sciences [16K18859]
- Grants-in-Aid for Scientific Research [16K18859] Funding Source: KAKEN
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We investigated the phase separation behavior and maintenance mechanism of the supersaturated state of poorly water-soluble nifedipine (NIF) in hypromellose (HPMC) derivative solutions. Highly supersaturated NIP formed NIF-rich nanodroplets through phase separation from aqueous solution containing HPMC derivative. Dissolvable NIF concentration in the bulk water phase was limited by the phase separation of NIF from the aqueous solution. HPMC derivatives stabilized the NIP-rich nanodroplets and maintained the NIF Super saturation with phase-separated NIP for several hours. The size of the NIF-rich phase was different depending on the HPMC derivatives dissolved in aqueous solution, although the droplet size had no correlation with the time for which NIF supersaturation was maintained without NIP crystallization. HPMC acetate and HPMC acetate succinate (HPMC-AS) effectively maintained the NIF supersaturation containing phase-separated NIF compared with HPMC. Furthermore, HPMC-AS stabilized NIF supersaturation more effectively in acidic conditions. Solution H-1 NMR. measurements of NIF-supersaturated solution revealed that HPMC derivatives distributed into the NIF-rich phase during the phase separation of NIP from the aqueous solution. The hydrophobicity of HPMC derivative strongly affected its distribution into the NIF-rich phase. Moreover, the distribution of HPMC-AS into the NIP-rich phase was promoted at lower pH due to the lower aqueons solubility of HPMC-AS. The distribution of a large amount of HPMC derivatives into NIF-rich phase induced the strong inhibition of NIF crystallization from the NIF-rich phase. Polymer distribution into the drug-rich phase directly monitored by solution NMR technique can be a useful index for the stabilization efficiency of drug-supersaturated solution containing a drug-rich phase.
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